Study suggests fibrinogen as a therapeutic target for myelin-related disorders

A study, carried out by researchers from the USA, Germany, and Australia, opens up a new avenue for treatment of neurological disorders like multiple sclerosis (MS).

Lead researcher of the study is Dr. Katerina Akassoglou, senior investigator at the Gladstone Institutes of Neurological Disease and professor of neurology at the University of California. Dr. Akassoglou has been studying the mechanisms of neurologic diseases like MS for years. In particular, she looks at the functions of the blood clotting factors in the central nervous system in health and disease.

MS and several other neurologic diseases result from the dysfunction or disruption of myelin, the insulating material around nerve cells. Myelin forms a sheath over the never fibers and functions to ensure that neural signals are transmitted rapidly and efficiently. When the myelin sheath is damaged, impairment of signal transmission occurs, leading to problems with memory, specific movements and other functions.

In the healthy central nervous system, there are several mechanisms to repair myelin damage and restore neural function. For example, a population of adult neural stem cells move to the damaged area and develop into myelin-producing cells to replace lost myelin sheaths. This regenerative process is important for maintenance of normal function of the myelin sheath. However, under disease conditions, these myelin repair mechanisms are blocked. Unraveling the mystery behind this would help combat MS and other neurologic diseases associated with myelin dysfunction.

Previous studies have mainly focused on activities within cells. The new study, instead, investigated the environment outside cells. It's known that if the blood-brain barrier is disrupted, molecules in the blood will enter the central nervous system, changing the composition of the brain microenvironment. Prior to the new study, Dr. Akassoglou discovered that fibrinogen, a blood clotting factor that circulates in the blood, can trigger inflammation and damage when blood leaks into the brain. However, it remains unclear whether blood-derived molecules like fibrinogen could inhibit the regeneration of myelin.

For the current study, Dr. Akassoglou's team demonstrated that fibrinogen suppresses myelin regeneration by stopping adult stem cells from developing into myelin-producing cells. Specifically, fibrinogen works through the BMP signaling pathway, and the effects of fibrinogen could be rescued by inhibiting this pathway. In vivo experiments showed that fibrinogen depletion could downregulate BMP signaling and promote the regeneration of myelin. Collectively, these data suggest fibrinogen as a blood-derived inhibitor of myelin regeneration. Thus, targeting fibrinogen might be a way to promote brain repair and treat neurologic diseases like MS.

This work was done in collaboration with the University of Miami Miller School of Medicine, Stanford University School of Medicine, National Institutes of Health, the University of Freiburg, and the Medical University of Vienna. The researchers concluded their findings in a paper titled "Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage," appearing 2 Nov. 2017 in the journal Neuron.
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